WO2002079517A1 - Methods and compositions for using mhc class ii invariant chain polypeptide as a receptor for macrophage migration inhibitory factor - Google Patents
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- WO2002079517A1 WO2002079517A1 PCT/US2002/009580 US0209580W WO02079517A1 WO 2002079517 A1 WO2002079517 A1 WO 2002079517A1 US 0209580 W US0209580 W US 0209580W WO 02079517 A1 WO02079517 A1 WO 02079517A1
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Definitions
- MHC class II invariant chain polypeptide, li also known as CD74
- MIF macrophage migration inhibitory factor
- Macrophage migration inhibitory factor (MIF)
- MIF Macrophage migration inhibitory factor
- MIF has been linked to cancer 32 .
- MIF is critically involved in the expression of innate and acquired
- MIF is released by a variety of cell types and is a necessary factor for the
- MIF -/- mice are highly resistant to endotoxic shock 3 , and immunoneutralization of
- MIF confers protection against septic shock 25 and a variety of immuno-inflammatory pathologies such as delayed-type hypersensitivity 26 , arthritis 27 , and glomerulonephritis 28 . MIF's actions on cells also show a number of
- MIF may function as an isomerase 4 .
- the MHC class Il-associated invariant chain, li (CD74) 10 has been
- the invention is based in part upon the identification, utilizing expression
- polypeptide, Ii (or CD74) 10 is a cellular receptor for MIF.
- MIF binds to the
- Ii extracellular domain of Ii, a Type II membrane protein, and Ii is required for
- MIF-induced cell activation and/or phenotypic changes including , for instance,
- the inventive relationship provides a mechanism for MIF's
- one aspect of the present invention relates to methods for
- a biochemical (i.e., acellular) binding assay comprising:
- MHC class II invariant chain (Ii) polypeptide contacting an MHC class II invariant chain (Ii) polypeptide with MIF in the presence and absence of a test compound, and comparing the binding interaction of
- an enhancer of MIF binding activity and a compound that negatively modulates the interaction of MIF with the Ii polypeptide is identified as an inhibitor of MIF
- Enhancers so identified are candidate therapeutic agonists or
- test compound may reinforce the binding of
- test compound that competes with MIF for binding to the Ii polypeptide or otherwise inhibits the interaction of the MIF with the Ii polypeptide
- the la polypeptide comprises the complete la sequence
- the binding assay may be a cellular binding assay
- CD74 expressed (either normally or as a consequence of genetic
- affinity is identified as an enhancer of MIF binding activity and a compound that
- the cellular assay is a signaling assay, in which the activity
- the signaling assay is an ERK-1/2 activation assay.
- Ii polypeptide is identified as an enhancer of MIF signaling activity and a
- Enhancers so identified are candidate therapeutic agonists or enhancers of MIF,
- inhibitors so identified are candidate therapeutic antagonists of MIF.
- the cellular assay is a cellular activity or cell phenotype
- the activity or phenotype assay is a
- a test compound that positively modulates the chosen cellular activity A test compound that positively modulates the chosen cellular activity
- phenotypic change mediated by MIF via interaction with the Ii polypeptide is identified as an enhancer of MIF cellular activity and a compound that negatively
- Enhancers so identified are candidate therapeutic agonists or enhancers of
- inhibitors so identified are candidate therapeutic antagonists of MIF.
- the invention also provides an enhancer of MIF, including an agonist, or an inhibitor, including an antagonist of MIF, identified by any of the methods above.
- an enhancer of MIF including an agonist, or an inhibitor, including an antagonist of MIF, identified by any of the methods above.
- One form of such an agonist or antagonist would be an antibody or antigen-binding
- Anti-CD74 antibodies and
- CD74-binding fragments thereof are known in the art.
- antibody may be a monoclonal antibody and also may be a human, humanized or
- chimeric antibody made by any conventional method.
- polypeptide which binds MIF and thereby mediates the effect of MIF.
- the antagonist or inhibitor inhibits, in a first instance, binding of MIF to the Ii polypeptide; in a second instance, signaling initiated by MIF:Ii interaction; and in a third instance, a change in cellular activity, metabolism or phenotype effected by
- the antagonist or inhibitor may be an
- inhibitor may be soluble Ii polypeptide or a soluble MIF-binding fragment thereof
- the cell comprising Ii
- polypeptide is present in a mammal and the antagonist or other inhibitor is
- the antagonist or inhibitor is administered in an amount effective to treat the condition or disorder.
- the mammal may be suffering from cancer or an
- the antagonist or inhibitor is administered in an amount
- septic shock may be, for instance, septic shock or arthritis.
- one aspect of the invention is a method of inhibiting an
- MIF activity of MIF which method comprises: contacting MIF with an MHC class II
- fragment of the MHC class II invariant chain (Ii) polypeptide which binds to MIF may be a soluble form of the polypeptide, particularly a soluble form that
- the MIF to be inhibited is in a mammal and the Ii
- polypeptide or a fragment thereof is administered to the mammal in a
- fragment thereof is administered in an amount effective to treat the disorder.
- the MIF antagonist or inhibitor is administered in an amount
- the infecting pathogen (whether a virus, bacterial, fungus, or especially, a parasite)
- Yet another aspect of the invention relates to a method of purifying MIF
- polypeptide may be immobilized on a solid support matrix.
- the invention also provides a solid support matrix.
- MIF:Ii polypeptide fragment complex thereby formed.
- Still another method provided by the invention is a method for reducing an
- This method comprises: providing to the cell an antisense nucleic
- the antisense nucleic acid molecule specifically binds to a
- the cell comprising the Ii polypeptide may be in a mammal, for instance, a mammal
- the mammal may be suffering from a cancer
- the inflammatory disorder such as septic shock or arthritis.
- the inflammatory disorder such as septic shock or arthritis.
- antisense nucleic acid is administered in a pharmaceutical composition, in an
- FIG. 1 illustrates high affinity binding of MIF to THP-1 monocytes.
- Alexa-MIF shows full retention of dose-dependent MIF biological activity as
- CM complete medium
- SFM serum-free medium
- Alexa-MIF binding was performed in the presence of 1 ⁇ g/ml unlabeled, rMIF
- THP-1 cells were grown on cover slips, incubated with INF ⁇ (1 ng/ml) for 72 hrs and stained with Alexa-MIF (left panel) or Alexa-MIF plus excess,
- FIG. 2 show that Ii is a cell surface binding protein for MIF a, Sequential
- IC, TM, and EC are the intracellular, transmembrane, and extracellular domains.
- Ml and Ml 7 refer to two sites of alternative translation initiation, c, Flow
- FIG. 3 illustraes Ii mediation of MIF stimulation of ERK-1/2 (p44/ ⁇ 42) ⁇
- COS-7 cells were transfected with an Ii vector and stimulated with 50 ng/ml MIF
- FIG. 4 illustrates western blots of MIF-induced phosphorylation a, MIF
- Anti-Ii inhibits MIF-induced proliferation of human
- fibroblasts also. Antibodies were added to a final concentration of 50 ⁇ g/ml. The
- FIG. 5 shows the complete nucleotide sequence (SEQ ID NO: 1)
- Alexa-MIF Alexa 488-MIF
- ERK extracellular-signal-regulated kinase
- Ii MHC class Il-associated invariant chain (CD74)
- INF ⁇ interferon- ⁇
- mAb monoclonal antibody
- MIF monoclonal antibody
- MIF binds to the extracellular domain of Ii, a Type II membrane protein, and Ii is
- IFN ⁇ interferon- ⁇
- THP-1 monocytes and constructed a mammalian expression library in the lambdaZAP-CMV vector 15 .
- Library aliquots representing a total of 1.5 x 10 7 recombinants were transfected into COS-7 cells, which we had established
- Anti-Ii mAb directed against the extracellular portion of the protein.
- binding epitope was localized to a 40 amino acid region contained within the Ii extracellular domain (FIG. 2D).
- MIF extends the lifespan of primary murine fibroblasts 8 , and both MIF's
- Fibroblasts express low levels of
- Ii is a homotrimer 23
- the Ii intracellular domain consists of 30-46 amino acids, depending on which of two in-phase
- initiation codons are utilized 16 .
- Monocyte-encoded Ii has been shown to enhance T cell proliferative responses, and this accessory function of Ii has been linked to a
- MIF-bound Ii is a stimulating ligand for CD44-mediated MAP kinase activation.
- CD44 is a highly polymorphic Type I transmembrane glycoprotein 24 , and CD44 likely mediates some of the downstream consequences of MIF binding to Ii.
- Agents active in this regard (agonists and antagonists and other inhibitors) have predicted therapeutic utility in diseases and conditions
- Trojan horse-type vehicles by which to concentrate a desired label or toxin in cells displaying cell surface Ii. Briefly, a desired label or toxic entity is associated
- invariant chain polypeptide binds to and causes the intemalization of the modified
- the Ii-displaying cells may be exposed to the modified MIF ligand in
- Ii-displaying cells may be specifically designed
- MIF ligand which may be
- chemotherapeutic drugs such as doxorubicin
- chelators such as DTP A, to which detectable labels such as fluorescent molecules or cytotoxic agents such as heavy metals or
- radionuclides can be complexed; and toxins such as Pseudomonas exotoxin, and
- Human recombinant MIF was purified from an E.coli expression system as
- homotrimer was 1 :3, as determined by matrix-assisted laser-desorption ionization
- THP-1 cells (2.5 xlO 5 cells/ml) were cultured in DMEM/10% FBS with or without
- IFN ⁇ (1 ng/ml, R&D Systems, Minneapolis, MN) for 72 hrs. After washing,
- transfectants were incubated with Alexa-MIF together with 50 ⁇ g/ml of an anti-Ii
- THP-1 cells (1 x 10 6 ) were incubated for 45 mins at 4°C in PBS/1%
- Alexa-MIF or Alexa-MIF plus 50 ng/ ⁇ l unlabeled, rMIF.
- cDNA was prepared from the poly(A) + RNA of IFN ⁇ -activated, THP-1
- dextran method 30 The transfected cells were incubated with Alexa-MIF for 45 min
- Plasmid DNA was extracted from sorted cells using the Easy DNA kit (Invitrogen,
- T ⁇ T Reticulocyte Lysate system (Promega, Madison WI). The binding of [ 35 S]- labeled Ii to immobilized MIF was assessed by a 3 hr incubation at room
- fibroblasts by immunoassay of cytoplasmic histone-associated D ⁇ A fragments (Roche Biochemicals, Indianapolis, IN) 8 . Proliferation studies were performed by a
- MIF inhibitory factor
- MIF inhibitory factor
- MIF macrophage migration inhibitory factor
- MIF murine lymphoma
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Abstract
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Priority Applications (7)
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AU2002255961A AU2002255961B2 (en) | 2001-03-29 | 2002-03-29 | Methods and compositions for using MHC class II invariant chain polypeptide as a receptor for macrophage migration inhibitory factor |
JP2002577925A JP4202763B2 (en) | 2001-03-29 | 2002-03-29 | Methods and compositions for the use of MHC class II invariant chain polypeptides as macrophage migration inhibitory factor receptors |
CA2455915A CA2455915C (en) | 2001-03-29 | 2002-03-29 | Methods and compositions for using mhc class ii invariant chain polypeptide as a receptor for macrophage migration inhibitory factor |
DK02725395.4T DK1383919T3 (en) | 2001-03-29 | 2002-03-29 | Methods and compositions for using MHC class II invariant chain polypeptide as a receptor for macrophage migration inhibitory factor |
EP02725395A EP1383919B1 (en) | 2001-03-29 | 2002-03-29 | Methods and compositions for using mhc class ii invariant chain polypeptide as a receptor for macrophage migration inhibitory factor |
DE60236921T DE60236921D1 (en) | 2001-03-29 | 2002-03-29 | METHOD AND COMPOSITIONS FOR USE OF MHC CLASS II INVARIANT CHAIN POLYPEPTIDE AS A RECIPE FOR MACROPHONE WALKING HEMM FACTOR |
AT02725395T ATE473294T1 (en) | 2001-03-29 | 2002-03-29 | METHOD AND COMPOSITIONS FOR USING MHC CLASS II INVARIANT CHAIN POLYPEPTIDE AS A MACROPHAGE MIGRATION INHIBITORY FACTOR RECEPTOR |
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US27943501P | 2001-03-29 | 2001-03-29 | |
US60/279,435 | 2001-03-29 |
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WO2002079517A1 true WO2002079517A1 (en) | 2002-10-10 |
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PCT/US2002/009580 WO2002079517A1 (en) | 2001-03-29 | 2002-03-29 | Methods and compositions for using mhc class ii invariant chain polypeptide as a receptor for macrophage migration inhibitory factor |
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US (10) | US20030013122A1 (en) |
EP (1) | EP1383919B1 (en) |
JP (1) | JP4202763B2 (en) |
AT (1) | ATE473294T1 (en) |
AU (1) | AU2002255961B2 (en) |
CA (1) | CA2455915C (en) |
DE (1) | DE60236921D1 (en) |
DK (1) | DK1383919T3 (en) |
ES (1) | ES2352228T3 (en) |
WO (1) | WO2002079517A1 (en) |
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US7084141B2 (en) | 2001-05-24 | 2006-08-01 | Avanir Pharmaceuticals | Inhibitors of macrophase migration inhibitory factor and methods for identifying the same |
JP2007504158A (en) * | 2003-08-29 | 2007-03-01 | サイトカイン・ファーマサイエンシズ・インコーポレーテッド | Treatment method and bioassay comprising macrophage migration inhibitory factor (MIF) as heart-derived myocardial suppressor |
US7235546B2 (en) | 2003-02-14 | 2007-06-26 | Avanir Pharmaceuticals | Inhibitors of macrophage migration inhibitory factor and methods for identifying the same |
US7365200B2 (en) | 2005-03-24 | 2008-04-29 | Avanir Pharmaceuticals | Thienopyridinone derivatives as macrophage migration inhibitory factor inhibitors |
EP2270505A1 (en) * | 2002-04-26 | 2011-01-05 | Takeda Pharmaceutical Company Limited | A method of screening a cell death inhibitor using macrophage migration inhibitory factor (MIF) |
US9238689B2 (en) | 2011-07-15 | 2016-01-19 | Morpho Sys AG | Antibodies that are cross-reactive for macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (D-DT) |
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US7312318B2 (en) * | 2002-03-01 | 2007-12-25 | Immunomedics, Inc. | Internalizing anti-CD74 antibodies and methods of use |
DE60236921D1 (en) * | 2001-03-29 | 2010-08-19 | Cytokine Pharmasciences Inc | METHOD AND COMPOSITIONS FOR USE OF MHC CLASS II INVARIANT CHAIN POLYPEPTIDE AS A RECIPE FOR MACROPHONE WALKING HEMM FACTOR |
US20160279239A1 (en) | 2011-05-02 | 2016-09-29 | Immunomedics, Inc. | Subcutaneous administration of anti-cd74 antibody for systemic lupus erythematosus and autoimmune disease |
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WO2007044622A1 (en) | 2005-10-07 | 2007-04-19 | Yale University | Use of mif and mif pathway agonists |
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EP3052526A4 (en) | 2013-10-03 | 2017-04-19 | Oregon Health & Science University | Recombinant polypeptides comprising mhc class ii 1 domains |
EP2944310B1 (en) | 2014-05-16 | 2018-03-21 | Mifcare | MIF inhibitors for the acute or chronic treatment of pulmonary hypertension |
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WO2015200260A1 (en) | 2014-06-24 | 2015-12-30 | Immunomedics, Inc. | Anti-histone therapy for vascular necrosis in severe glomerulonephritis |
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WO2017070569A1 (en) * | 2015-10-23 | 2017-04-27 | Oregon Health & Science University | Compounds that bind macrophage migration inhibitory factor |
CN110352201A (en) | 2017-04-03 | 2019-10-18 | 免疫医疗公司 | The subcutaneous administration of antibody drug conjugate for cancer therapy |
CN114668832A (en) * | 2022-04-27 | 2022-06-28 | 西安市第一医院 | Application of MIF and receptor CD74 thereof in preparation of drugs for regulating cell function and dividing proliferation |
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US6492428B1 (en) * | 2000-07-26 | 2002-12-10 | The Picower Institute For Medical Research | Compounds having MIF antagonist activity |
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US6326465B1 (en) * | 1997-02-24 | 2001-12-04 | The Johns Hopkins University | Immunomodulatory polypeptides derived from the invariant chain of MHC class II |
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- 2002-03-29 CA CA2455915A patent/CA2455915C/en not_active Expired - Lifetime
- 2002-03-29 AU AU2002255961A patent/AU2002255961B2/en not_active Expired
- 2002-03-29 US US10/108,383 patent/US20030013122A1/en not_active Abandoned
- 2002-03-29 DK DK02725395.4T patent/DK1383919T3/en active
- 2002-03-29 AT AT02725395T patent/ATE473294T1/en active
- 2002-03-29 EP EP02725395A patent/EP1383919B1/en not_active Expired - Lifetime
- 2002-03-29 JP JP2002577925A patent/JP4202763B2/en not_active Expired - Fee Related
- 2002-03-29 WO PCT/US2002/009580 patent/WO2002079517A1/en active Application Filing
- 2002-03-29 ES ES02725395T patent/ES2352228T3/en not_active Expired - Lifetime
-
2005
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2008
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2010
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2011
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2014
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2015
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2016
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Cited By (22)
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US7235565B2 (en) | 2001-05-24 | 2007-06-26 | Avanir Pharmaceuticals | Inhibitors of macrophage migration inhibitory factor and methods for identifying the same |
US7129236B2 (en) | 2001-05-24 | 2006-10-31 | Avanir Pharmaceuticals | Inhibitors of macrophage migration inhibitory factor and methods for identifying the same |
US7238809B2 (en) | 2001-05-24 | 2007-07-03 | Avanir Pharmaceuticals | Process for the preparation of inhibitors of macrophage migration inhibitory factor |
US7157469B2 (en) | 2001-05-24 | 2007-01-02 | Avanir Pharmaceuticals | Inhibitors of macrophage migration inhibitory factor and methods for identifying the same |
US7084141B2 (en) | 2001-05-24 | 2006-08-01 | Avanir Pharmaceuticals | Inhibitors of macrophase migration inhibitory factor and methods for identifying the same |
US7192961B2 (en) | 2001-05-24 | 2007-03-20 | Avanir Pharmaceuticals | Inhibitors of macrophage migration inhibitory factor and methods for identifying the same |
US7192955B2 (en) | 2001-05-24 | 2007-03-20 | Avanir Pharmaceuticals | Inhibitors of macrophage migration inhibitory factor and methods for identifying the same |
US7202248B2 (en) | 2001-05-24 | 2007-04-10 | Avanir Pharmaceuticals | Inhibitors of macrophage migration inhibitory factor and methods for identifying the same |
US7732146B2 (en) | 2001-05-24 | 2010-06-08 | Avanir Pharmaceuticals | Method for screening an agent that modulates activity of macrophage migration inhibitory factor |
US7514225B2 (en) | 2001-05-24 | 2009-04-07 | Avanir Pharmaceuticals | Method for screening an agent that modulates activity of macrophage migration inhibitory factor |
US7435737B2 (en) | 2001-05-24 | 2008-10-14 | Avanir Pharmaceutials | Inhibitors of macrophage migration inhibitory factor and methods for identifying the same |
US7105519B2 (en) | 2001-05-24 | 2006-09-12 | Avanir Pharmaceuticals | Inhibitors of macrophage migration inhibitory factor and methods for identifying the same |
US7230106B2 (en) | 2001-05-24 | 2007-06-12 | Avanir Pharmaceuticals | Process for the preparation of inhibitors of macrophage migration inhibitory factor |
US7432374B2 (en) | 2001-05-24 | 2008-10-07 | Avanir Pharmaceuticals | Inhibitors of macrophage migration inhibitory factor and methods for identifying the same |
EP2270505A1 (en) * | 2002-04-26 | 2011-01-05 | Takeda Pharmaceutical Company Limited | A method of screening a cell death inhibitor using macrophage migration inhibitory factor (MIF) |
US8173360B2 (en) | 2002-04-26 | 2012-05-08 | Takeda Pharmaceutical Company Limited | Cell death inhibitor |
US7312221B2 (en) | 2003-02-14 | 2007-12-25 | Avanir Pharmaceuticals | Inhibitors of macrophage migration inhibitory factor and methods for identifying the same |
US7235546B2 (en) | 2003-02-14 | 2007-06-26 | Avanir Pharmaceuticals | Inhibitors of macrophage migration inhibitory factor and methods for identifying the same |
US7312220B2 (en) | 2003-02-14 | 2007-12-25 | Avanir Pharmaceuticals | Inhibitors of macrophage migration inhibitory factor and methods for identifying the same |
JP2007504158A (en) * | 2003-08-29 | 2007-03-01 | サイトカイン・ファーマサイエンシズ・インコーポレーテッド | Treatment method and bioassay comprising macrophage migration inhibitory factor (MIF) as heart-derived myocardial suppressor |
US7365200B2 (en) | 2005-03-24 | 2008-04-29 | Avanir Pharmaceuticals | Thienopyridinone derivatives as macrophage migration inhibitory factor inhibitors |
US9238689B2 (en) | 2011-07-15 | 2016-01-19 | Morpho Sys AG | Antibodies that are cross-reactive for macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (D-DT) |
Also Published As
Publication number | Publication date |
---|---|
US20110020321A1 (en) | 2011-01-27 |
CA2455915A1 (en) | 2002-10-10 |
DK1383919T3 (en) | 2010-11-08 |
AU2002255961B2 (en) | 2007-08-23 |
US8617822B2 (en) | 2013-12-31 |
CA2455915C (en) | 2013-05-14 |
US20160152708A1 (en) | 2016-06-02 |
US20120039914A1 (en) | 2012-02-16 |
US8779099B2 (en) | 2014-07-15 |
US20090263404A1 (en) | 2009-10-22 |
JP4202763B2 (en) | 2008-12-24 |
EP1383919A1 (en) | 2004-01-28 |
US20150010570A1 (en) | 2015-01-08 |
EP1383919B1 (en) | 2010-07-07 |
ES2352228T3 (en) | 2011-02-16 |
US20060024754A1 (en) | 2006-02-02 |
US20080146507A1 (en) | 2008-06-19 |
DE60236921D1 (en) | 2010-08-19 |
US20180105593A1 (en) | 2018-04-19 |
US7741057B2 (en) | 2010-06-22 |
US9221903B2 (en) | 2015-12-29 |
JP2004532839A (en) | 2004-10-28 |
ATE473294T1 (en) | 2010-07-15 |
EP1383919A4 (en) | 2004-12-01 |
US20140178403A1 (en) | 2014-06-26 |
US20030013122A1 (en) | 2003-01-16 |
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